Summary Motor dysfunction is prevalent in combination antiretroviral therapy (cART) era HIV+ populations, however, its genesis is unclear, as cerebrovascular disease is likely to contribute to its etiology. We propose to study the spectrum, underlying neural circuitry, and cell type-specific molecular signatures of HIV-associated motor dysfunction, with the following aims and hypotheses: Aim 1. Identify neural regions associated with motor impairment in HIV+ patients with and without cerebrovascular disease. 160 cART-treated subjects will be recruited to a structural and functional magnetic resonance imaging study, to test the hypothesis that the neuroanatomical basis of motor task performance will vary by motor status (normal/abnormal) and presence or absence of cerebrovascular comorbidity. For this 2x2 analysis, participants in the Manhattan HIV Brain Bank (MHBB) will form a nidus for recruitment, with multimodal assessment of motor function. These analyses will be conducted in years 1 and 2. Then, having identified regions most strongly implicated in motor dysfunction, in years 3 through 5 we will examine autopsy brains from the MHBB cohort for: Aim 2. Cell-type specific transcriptome and epigenome mapping in dorsolateral striatum, ventral midbrain, and selected gray and white matter regions of interest (ROI) as defined in aim 1 to identify molecular signatures of motor dysfunction. Our hypothesis is that the molecular genesis of motor dysfunction can be elucidated through regional and cell-type specific analysis of transcriptome and open chromatin-associated histone acetylation and methylation landscape. Specifically, that neuronal, astrocyte, and oligodendrocyte signatures in HIV+ brain regions implicated in motor function will be affected by HIV-inflammatory burden and regional cerebrovascular disease; and that motor function will be predicted by these regional changes. Fluorescence-activated nuclei sorting in neuroanatomic regions implicated in motor dysfunction will be used for cell-type specific fractions of input material for genome-scale RNA-Seq and histone ChIP-seq. In contiguous tissue, assays of HIV DNA by nested PCR, monocyte/microglial cell activation by CD68 and CD163 immunohistochemistry, and cerebral small vessel disease (CSVD) by morphometric analysis of arteriolar wall thickening, will be done. 100 MHBB HIV+ brains will be selected on the basis of cognitive profiles and vascular risk to best approximate living subjects in aim #1, along with brains accrued from imaged individuals through subsequent organ donation. 50 demographically similar HIV- brains will also be studied. Candidate genes in molecular signatures of motor dysfunction with and without vascular disease will be tested via qPCR. With these aims, we will elucidate the neural circuitry of motor dysfunction in cART-treated HIV, cerebrovascular contributions to its genesis, and characterize its regional neurogenomics. Insight into molecular alterations and targets for amelioration will be relevant to a wider spectrum of neurodegenerative disorders with vascular contributions in HIV- populations.